Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
This invention relates to methods for specifically altering the immune system response of a mammal wherein specific forms of immune suppression in the mammal are elicited when the mammal is actively immunized in response to a specific antigen.
An immune response may be classified as either a humoral response or a cell-mediated response. A humoral response is one which is mediated by freely diffusible antibody molecules. A cell-mediated response is mediated by specifically reactive lymphocytes, such as T cells, rather than antibodies.
Basic differences exist between humoral and cell-mediated reactions. The time course from exposure to an antigen until the formation of an immune response is minutes to hours for humoral immunity and one or more days for cell-mediated immunity. The active unit which reacts with the antigen is an antibody in humoral immunity and a T lymphocyte in cell-mediated immunity. Humoral antibodies are generally specific for small antigenic determinants. T lymphocytes are specific for larger molecules, usually proteins (in particular, those carried on cell surfaces).
While a cell-mediated response is generally a beneficial part of the body's defenses, certain cell-mediated responses are harmful. Examples of such harmful cell-mediated immune responses include delayed-type hypersensitivity reactions, rejections of allografts, graft-vs.-host reactions and some allergic reactions. Additionally, some autoimmune diseases are also included, such as myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus and Grave's disease.
Many of these harmful cell-mediated responses involve tissue destruction in a patient and understandably, it would be desirable to eliminate or reduce the effect of such a response. One such response that is of interest is the rejection of allografts. An allograft is a cell, tissue or organ that is transferred from a donor to a genetically different recipient of the same species. Because of extensive polymorphism of certain surface glycoproteins, the grafted cells almost always have on their surfaces histocompatibility or transplantation antigens that are lacking on host cells and vice versa. The resulting host response leads to destruction of the allograft through a cell mediated response.
The graft-vs.-host reaction occurs when lymphocytes are transferred from an immunologically competent donor (normal adult) to an allogeneic incompetent recipient (e.g. newborn). These reactions have increasing clinical importance because of therapeutic attempts to transfer normal thymus or bone marrow cells to immunodeficient humans (e.g., infants with genetic defects, patients with leukemia treated with cytotoxic drugs and whole-body x-irradiation).
In autoimmune disorders, the immune system of the body fails to recognize certain cells or parts of cells as its own and begins attacking those cells with resulting tissue destruction. This attack is effected by the production of autoantibodies and autoreactive T cells.
Allergic responses involve a heightened immune response. In some allergic responses, the immune system mounts an attack against a normally harmless substance, such as pollen, animal dander or dust. In these allergic responses, sensitized T lymphocytes react with the antigen and produce inflammation through the action of lymphokines. Disease results from the deleterious effect of the resulting inflammatory reaction to these environmental antigens. An example of such a reaction is allergic contact dermatitis.
The present invention provides a method for specifically altering the immune response of a patient resulting in the amelioration of a specific immune disorder and thereby the deleterious effects of the disorder.
U.S. Pat. Nos. 4,321,919; 4,398,906; 4,428,744; and 4,464,166 (each in the name of Edelson), the contents of each of which is hereby incorporated by reference in its entirety, describe methods for reducing the functioning lymphocyte population of a human subject. The Edelson methods involve treating the blood of a diseased patient wherein the blood cells have been naturally stimulated as a consequence of the disease state. Specifically, the methods involve treating naturally stimulated human blood cells, such as lymphocytes, with a dissolved photoactivatable drug, such as a psoralen, which is capable of forming photoadducts with DNA in the presence of ultraviolet (U.V.) radiation. The lymphocytes are then treated extracorporeally with U.V. radiation thereby modifying the lymphocytes. Following the extracorporeal irradiation, the treated lymphocytes are returned to the patient. The modified lymphocytes are thought to be cleared from the subject's system by natural processes but at an accelerated pace believed attributable to disruption of membrane integrity, alteration of DNA within the cells, or the like conditions often associated with substantial loss of cellular effectiveness or viability.
The methods described in the Edelson patents have recently been used in human clinical studies in patients afflicted with the erythrodermic (Sezary) form of cutaneous T cell lymphoma (CTCL). The results indicated that the method reduced all T cell populations within the patients, but the normal populations of T cells rebounded within four weeks and suppression of malignant cells was more lasting.
A disadvantage of the methods described by Edelson is that they are not suitable for prophylactic use. For example, the Edelson methods cannot be used to selectively suppress the immune system response of a patient to a specific antigen which is characterisitc of an immune disorder and to which the patient has not yet been exposed.
Studies in rodent systems have shown that the intravenous infusion of syngeneic cells from in vitro expanded auto-reactive clones of T cells can induce experimental autoimmune thyroiditis, encephalomyelitis or arthritis (Cohen, IR. Adv. Intern. Med. (1984) 29: 147-165.) However, if cultured cells from the same T cell clones are lethally damaged or attenuated by treatment with irradiation or mitomycin C to form a vaccine and then infused into syngeneic mice or rats, the recipient animal develops resistance to the induction of the disease by the subsequent infusion of viable auto-reactive T cells (Ben-nun, A. et al., Nature (1981), 292: 60-61; Holoshitz, J. et al., Science (1983), 219: 56-58; and Cohen, I. R., J. Invest. Derm (1985), 85 (Supp. 1): 34s-38s). Thus, it has been demonstrated that cell lines of treated autoimmune effector T cells may be used to vaccinate against the autoimmune disorder.
The rodent experiments described above have the disadvantage of requiring the isolation and growth of T cell lines which are capable of producing autoimmune disease. Such cell lines are not readily available for human diseases and can only be obtained, if at all possible, through time consuming effort. Therefore, the methods described in these rodent experiments are not suitable for treating humans. Furthermore, if such human T cell lines could be obtained, a different cell line specific for each autoimmune diseases treated would have to be prepared.
In further rodent experiments, it has been recently shown that the intravenous infusion of 8-methoxypsoralen (8-MOP) and subsequently U.V. treated lymphocytes into syngeneic MRL mice substantially inhibits the development of their systemic lupus erythematosus-like syndrome and lymphoid hyperplasia which they spontaneously develop (Perez, M. et al., Clin. Res. (1986) 34: 774A).
A pilot study described in Parrish, J. A. et al., N. Engl. J. Med (1974), 291: 1207-1211, indicated that combining oral administration of 8-MOP with ultraviolet-A (UVA) exposure of the skin is efficacious in the management of debilitating psoriasis vulgaris, a hyperproliferative disease of the epidermis. This was subsequenly confirmed in a multi-institutional clinical trial (Melski, J. W. et al. J. Invest. Derm. (1977), 68: 328-335). Subsequently, it was also demonstrated that plaque stage cutaneous T cell lymphoma (CTCL), limited to the skin, also responds to this treatment (Gilchrest B. A., et al. Cancer (1976) 38: 683-689; Honigsmann H., et al. J. Am. Acad. Derm. (1984) 10:238-245).
The prior art describes that lymphocytes may be disabled in diseased patients or may be attenuated to create vaccines. However, such knowledge is not useful in preventing disease in humans. The present invention has the advantage of being suitable for selectively preventing immune disorders in human patients. Furthermore, the present invention relies on the convenient stimulation of the patient's own immune system to produce stimulated lymphocytes rather than using time consuming cell culture techniques. Thus, the present invention provides a convenient method for preventing immune disorders which is suitable for being used for treating any immune disorder.